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Mol Syst Biol. 2014 Dec 23;10:772. doi: 10.15252/msb.20145450.

ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma.

Author information

1
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
2
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands Netherlands Proteomics Centre, Utrecht, The Netherlands Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
3
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands Netherlands Proteomics Centre, Utrecht, The Netherlands.
4
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, The Netherlands Netherlands Proteomics Centre, Utrecht, The Netherlands m.altelaar@uu.nl d.peeper@nki.nl.
5
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands m.altelaar@uu.nl d.peeper@nki.nl.

Abstract

Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down-regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies.

KEYWORDS:

PLX4720; ROCK1; kinome shRNA genomic screening; proteomics

PMID:
25538140
PMCID:
PMC4300494
DOI:
10.15252/msb.20145450
[Indexed for MEDLINE]
Free PMC Article

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